Effects of Apatinib combined with Temozolomide on levels of sPD-1 and sPD-L1 in patients with drug-resistant recurrent glioblastoma.

OBJECTIVE: This study aimed to explore the effects of Apatinib combined with Temozolomide (TMZ) on the levels of Soluble PD-1 (sPD-1) and Soluble Programmed Death-1 Ligand (sPD-L1) in patients with drug-resistant recurrent Glioblastoma (GB). STUDY DESIGN: A total of 69 patients with recurrent GB from September 2020 to March 2022 were recruited and assigned to the control group (n = 34) and observation group (n = 35) according to different treatment options after tumor recurrence. The control group was treated with TMZ, and the observation group was treated with Apatinib combined with TMZ. Levels of sPD-1 and spd-l1, clinical efficacy, survival time and adverse reactions were observed and compared between the two groups. RESULTS: General data including gender, age, body mass index, and combined diseases indicated no statistical significance between groups (p > 0.05). Before the intervention, sPD-1 and sPD-L1 levels were not significantly different in the two groups (p > 0.05). After interventions, levels of PD-1 and sPD-L1 levels decreased significantly (p < 0.05). The objective remission rate and clinical benefit rate of the observation group were higher and overall survival and progression-free survival were longer than those of the control group (p < 0.05). No significant difference was observed in major adverse reactions among patients (p > 0.05). CONCLUSIONS: Apatinib combined with TMZ is safe and effective in the treatment of recurrent GB. The combined application of the two can reduce the levels of sPD-1 and sPD-L1, which has important clinical application value.

Extensive neutralization against SARS-CoV-2 variants elicited by Omicron-specific subunit vaccine as a heterologous booster.

To overcome the increased risk of SARS-CoV-2 reinfection or post-vaccination infection caused by the Omicron variant, Omicron-specific vaccines were considered a potential strategy. We reported the increased magnitude and breadth of antibody response against VOCs elicited by post-vaccination Delta and Omicron infection, compared to WT infection without vaccination. Then, in mouse models, three doses of Omicron-RBD immunization elicited comparable neutralizing antibody (NAb) titers with three doses of WT-RBD immunization, but the neutralizing activity was not cross-active. By contrast, a heterologous Omicron-RBD booster following two doses of WT-RBD immunization increased the NAb titers against Omicron by 9-folds than the homologous WT-RBD booster. Moreover, it retains neutralization against both WT and current VOCs. Results suggest that Omicron-specific subunit booster shows its advantages in the immune protection from both WT and current VOCs and that SARS-CoV-2 vaccines including two or more virus lineages might improve the NAb response.

Timing of Tracheostomy in Patients with Intracerebral Haemorrhage: A Propensity-Matched Analysis.

AIMS: Although early tracheostomy (ET) is recommended for patients with severe stroke, the optimal timing of tracheostomy for patients with intracerebral haemorrhage (ICH) remains controversial. This study aimed to explore the clinical characteristics, risk factors and timing of tracheostomy in patients after tracheal intubation using a propensity-matched analysis. METHODS: We conducted a retrospective database search and assessed 267 consecutive patients who underwent endotracheal intubation (175 of whom underwent tracheostomy) and ICH between July 2017 and June 2021. A logistic regression model was applied to identify the critical factors influencing the decision for tracheostomy by comparing factors in a tracheostomy group and a nontracheostomy group. Patients were divided into an early (≤5 days) or a late (>5 days) group according to the median time of tracheostomy. Propensity score matching was performed to adjust for possible confounders and investigate differences in outcomes between ET and late tracheostomy (LT). RESULTS: Among the 267 enrolled patients with ICH and endotracheal intubation, 65.5% received tracheostomy during hospitalisation, and 52.6% received ET. The independent risk factors for tracheostomy included National Institute of Health Stroke Scale (NIHSS) (odds ratio [OR]: 1.179; 95% confidence interval [CI]: 1.028-1.351; P = 0.018), aspiration (OR: 2.171; 95% CI: 1.054-4.471; P = 0.035) and infiltrates (OR: 2.149; 95% CI: 1.088-4.242; P = 0.028). Using propensity matching, we found that ET was associated with fewer antibiotic-using days (15 vs. 18; P < 0.001) and sedativeusing days (6 vs. 8; P < 0.001), shorter intensive care unit (ICU) Length of Study (LOS) (9 vs. 12; P < 0.05) and reduced in-ICU costs (3.59 vs. 7.4; P < 0.001) and total hospital costs (8.26 vs. 11.28, respectively; P < 0.001). Muscle relaxants (31.8% vs. 60.6%) were used less frequently in patients with ET (P = 0.001). However, there were no differences between the ET and LT groups in terms of modified Rankin Scale (mRS) (4 vs. 4; P = 0.932), in-general-ward costs (4.74 vs. 4.37; P = 0.052), mechanical ventilation days (6 vs. 6; P = 0.961) and hospital LOS (23 vs. 23; P = 0.735) as well as the incidences of ventilator-associated pneumonia (28.8% vs. 37.9%; P = 0.268), tracheostomyrelated complications (16.7% vs. 19.7%; P = 0.652), respiratory failure (24.2% vs. 31.8%; P = 0.333), all-cause deaths (15.2% vs. 16.7%; P = 0.812) and pneumonia (77.3% vs. 87.9%; P = 0.108). CONCLUSION: We recommend ET for high-risk patients with ICH. Although ET cannot reduce inhospital mortality or improve patient prognosis, it may help reduce hospital costs and ICU LOS as well as the use of antibiotics, sedatives and muscle relaxants.

Effect of antiplatelet treatment on aneurysmal subarachnoid hemorrhage patients after endovascular treatment: a systematic review with meta-analysis.

Antiplatelet treatment (APT) has been reported to be used in some patients with aneurysmal subarachnoid hemorrhage (aSAH) after endovascular treatment, but there is controversy among different studies regarding its clinical effects. This study intends to conduct a meta-analysis to evaluate the impact of APT on aSAH patients after endovascular treatment. The PubMed, EMBASE, and Cochrane Library databases were systematically searched up to January 2022 for eligible English publications. Quality assessment was conducted for the included studies. Publication bias and heterogeneity were assessed by Egger's test and the I2 statistic, respectively. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated by meta-analysis. Robustness was checked by subgroup and sensitivity analyses. In total, 597 and 522 patients with and without APT, respectively, in 5 retrospective studies were retained for the meta-analysis. Pooled analyses showed that the APT group had a lower mortality (41/499 [8%] versus 56/402 [14%]; OR = 0.533; 95% CI, 0.347-0.820; P = 0.004) and a higher proportion of favorable clinical outcomes (400/532 [75%] versus 266/421 [63%]; OR = 1.801; 95% CI, 1.359-2.414; P = 0.000) than the control group. There was no significant difference in the incidence of hemorrhagic complications (39/564 [7%] versus 26/503 [5%]; OR = 1.386; 95% CI, 0.825-2.329; P = 0.218) between groups. Although the incidence of delayed cerebral ischemia (DCI) was significantly lower in the APT group (65/512 [13%] versus 105/447 [23%]; OR = 0.325; 95% CI, 0.107-0.988; P = 0.048), it showed substantial heterogeneity (I2 = 64.7%). Subsequent sensitivity analysis suggested that the meta-analysis was robust. Subgroup analyses revealed that long-term (> 2 weeks) APT (60/479 [13%] versus 103/428 [24%]; OR = 0.212; 95% CI, 0.056-0.806; P = 0.023) significantly reduced the DCI rate and that different grouping methods in the included studies may be a source of heterogeneity. In the absence of randomized controlled trials, a meta-analysis of retrospective studies suggested that APT was associated with reduced mortality and better functional outcomes in aSAH patients after endovascular treatment without an increased incidence of hemorrhagic complications. Long-term APT was also associated with a decrease in the incidence of DCI. Well-designed randomized controlled trials are warranted and updated meta-analyses are needed to verify our findings.

Ruptured intracranial aneurysm presenting as cerebral circulation insufficiency: A case report.

BACKGROUND: Rupture of an intracranial aneurysm is a type of acute stroke that is a serious threat to human health. Misdiagnosis of ruptured intracranial aneurysms is a serious clinical event that may have disastrous consequences in some patients. To date, ruptured intracranial aneurysms have been misdiagnosed as meningitis, tumors, stroke, or trauma, among other conditions. Here, we report what appears to be the first case of a ruptured intracranial aneurysm that presented as cerebral circulation insufficiency. CASE SUMMARY: A middle-aged man was admitted to our hospital because of a parasellar lesion identified on a noncontrast computed tomography (CT) image after a mild traffic accident that was caused by a brief loss of consciousness. Notably, he was diagnosed with cerebral circulation insufficiency after two unexplained episodes of a transient loss of consciousness within the past 8 mo. The patient was diagnosed with right internal carotid artery aneurysm based on CT angiography and completely recovered after a craniotomy at our hospital. A few clots and severe adhesions around the aneurysm were observed in the subarachnoid space during the operation, suggesting that the aneurysm had ruptured and may had been misdiagnosed as cerebral circulation insufficiency. CONCLUSION: Ruptured intracranial aneurysms may show negative imaging results and present as cerebral circulation insufficiency, which should be recognized as soon as possible to ensure timely management.

KDM6B promotes ESCC cell proliferation and metastasis by facilitating C/EBPß transcription.

BACKGROUND: As an H3K27me3 demethylase and counteracts polycomb-mediated transcription repression, KDM6B has been implicated in the development and malignant progression in various types of cancers. However, its potential roles in esophageal squamous cell carcinoma (ESCC) have not been explored. METHODS: The expression of KDM6B in human ESCC tissues and cell lines was examined using RT-qPCR, immunohistochemical staining and immunoblotting. The effects of KDM6B on the proliferation and metastasis of ESCC were examined using in vitro and in vivo functional tests. RNA-seq and ChIP-seq assay were used to demonstrate the molecular biological mechanism of KDM6B in ESCC. RESULTS: We show that the expression level of KDM6B increased significantly in patients with lymph node metastasis. Furthermore, we confirmed that KDM6B knockdown reduces proliferation and metastasis of ESCC cells, while KDM6B overexpression has the opposite effects. Mechanistically, KDM6B regulates TNFA_SIGNALING_VIA_NFκB signalling pathways, and H3K27me3 binds to the promoter region of C/EBPß, leading to the promotion of C/EBPß transcription. Besides, we show that GSK-J4, a chemical inhibitor of KDM6B, markedly inhibits proliferation and metastasis of ESCC cells. CONCLUSIONS: The present study demonstrated that KDM6B promotes ESCC progression by increasing the transcriptional activity of C/EBPß depending on its H3K27 demethylase activity.

Combined Metabolite and Transcriptome Profiling Reveals the Norisoprenoid Responses in Grape Berries to Abscisic Acid and Synthetic Auxin.

The abscisic acid (ABA) increase and auxin decline are both indicators of ripening initiation in grape berry, and norisoprenoid accumulation also starts at around the onset of ripening. However, the relationship between ABA, auxin, and norisoprenoids remains largely unknown, especially at the transcriptome level. To investigate the transcriptional and posttranscriptional regulation of the ABA and synthetic auxin 1-naphthaleneacetic acid (NAA) on norisoprenoid production, we performed time-series GC-MS and RNA-seq analyses on Vitis vinifera L. cv. Cabernet Sauvignon grape berries from pre-veraison to ripening. Higher levels of free norisoprenoids were found in ABA-treated mature berries in two consecutive seasons, and both free and total norisoprenoids were significantly increased by NAA in one season. The expression pattern of known norisoprenoid-associated genes in all samples and the up-regulation of specific alternative splicing isoforms of VviDXS and VviCRTISO in NAA-treated berries were predicted to contribute to the norisoprenoid accumulation in ABA and NAA-treated berries. Combined weighted gene co-expression network analysis (WGCNA) and DNA affinity purification sequencing (DAP-seq) analysis suggested that VviGATA26, and the previously identified switch genes of myb RADIALIS (VIT_207s0005g02730) and MAD-box (VIT_213s0158g00100) could be potential regulators of norisoprenoid accumulation. The positive effects of ABA on free norisoprenoids and NAA on total norisoprenoid accumulation were revealed in the commercially ripening berries. Since the endogenous ABA and auxin are sensitive to environmental factors, this finding provides new insights to develop viticultural practices for managing norisoprenoids in vineyards in response to changing climates.

Kinetic Characteristics of Neutralizing Antibody Responses Vary among Patients with COVID-19.

OBJECTIVE: The coronavirus disease 2019 (COVID-19) pandemic continues to present a major challenge to public health. Vaccine development requires an understanding of the kinetics of neutralizing antibody (NAb) responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). METHODS: In total, 605 serum samples from 125 COVID-19 patients (from January 1 to March 14, 2020) varying in age, sex, severity of symptoms, and presence of underlying diseases were collected, and antibody titers were measured using a micro-neutralization assay with wild-type SARS-CoV-2. RESULTS: NAbs were detectable approximately 10 days post-onset (dpo) of symptoms and peaked at approximately 20 dpo. The NAb levels were slightly higher in young males and severe cases, while no significant difference was observed for the other classifications. In follow-up cases, the NAb titer had increased or stabilized in 18 cases, whereas it had decreased in 26 cases, and in one case NAbs were undetectable at the end of our observation. Although a decreasing trend in NAb titer was observed in many cases, the NAb level was generally still protective. CONCLUSION: We demonstrated that NAb levels vary among all categories of COVID-19 patients. Long-term studies are needed to determine the longevity and protective efficiency of NAbs induced by SARS-CoV-2.

Development and validation of an early predictive nomogram for delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage.

BACKGROUND: Previous studies have shown that platelet is involved in the occurrence and progression of delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH), but the relationship between platelet and DCI is not completely clear. Here, we aimed to screen the early platelet parameters associated with DCI after aSAH and develop an early predictive nomogram for DCI after aSAH. METHODS: The study was carried out in the neurosurgery department of Affiliated Hospital of North Sichuan Medical College. A total of 285 consecutive aSAH patients admitted within 24 hours after onset were analyzed retrospectively. Univariate and multivariate analyses were used to identify risk factors for DCI. A predictive nomogram was developed and validated with R software. RESULTS: Sixty-six (23.16%) of the 285 patients with aSAH exhibited DCI during hospitalization. The DCI group and the non-DCI group showed statistically significant differences in red blood cell count (RBC), platelet count (PLT), mean platelet volume (MPV), modified Fisher grade and platelet distribution width (PDW). Multivariable logistic regression analysis showed that modified Fisher grade [odds ratio (OR) =1.354; 95% confidence interval (CI): 1.034-1.773; P=0.028] and mean MPV [OR =1.825; 95% CI: 1.429-2.331; P<0.001] were independent risk factors for DCI. Modified Fisher grade, RBC, PLT, MPV, and PDW were used to develop a predictive nomogram for DCI. The area under the receiver operating characteristic (ROC) curve (AUC) was 0.799 (95% CI: 0.737-0.861) in the training set and 0.783 (95% CI: 0.616-0.949) in the validation set. The calibration curve showed that the predicted probability concurred with the actual probability. Decision curve analysis indicated that this nomogram had good clinical application value and could be used for clinical decision making. CONCLUSIONS: Our study found that MPV was an early predictor of DCI after aSAH. The nomogram incorporating early MPV had greater value in predicting DCI after aSAH.

[Identification of the priority conservation areas of national park: A case study of Lishui City, Zhejiang Province, China]. / å›½å®¶å ¬å›­ä¼˜å ˆä¿æŠ¤åŒºåŸŸè¯†åˆ«­­ä»¥æµ™æ±Ÿä¸½æ°´ä¸ºä¾‹.

It is the goal of protected area management to make full use of limited resources to better protect biodiversity. Currently, the main tasks of developing national park system in China are to combine conservation features, optimize the spatial network of protected areas, and identify the prio-rity conservation areas of national parks effectively. In this study, we assessed the spatial distribution of key ecosystem services (carbon sequestration, oxygen release, hydrological regulation, water resources, and soil retention) using ecological model, and simulated the distribution of suitable habitats for 37 endangered species by MaxEnt in Lishui City, Zhejiang Province. The irreplaceability index of each planning unit in Lishui was calculated on the 0.4 km×0.4 km grid using the systema-tic conservation planning model (MARXAN), setting key ecosystem services and endangered species as the conservation objects. Combined with the local management needs, the priority protection areas of national parks were identified comprehensively. The results showed that during 2005 to 2015, the annual carbon storage, oxygen release, hydrological regulation, water resource, and soil retention in the study area was 0.05 kg C·m-2·a-1, 0.13 kg O2·m-2·a-1, 83.25×108 m3·a-1, 803 mm·a-1, and 95.53 t·hm-2·a-1, respectively. The irreplaceability index of different land use types was significantly different. The irreplaceability index of forest, river and reservoir, garden, cultivated land, residential land was 50-100, 60-100, 30-50, 15-35, 0-25, respectively. The priority conservation areas accounted for 11.8% of the study area. This study put forward a systematic conservation planning idea combining biodiversity and ecosystem services, which could provide a useful framework and technical support for optimizing the network layout of protected areas and priority conservation areas of national parks, and help to enhance the overall effectiveness of the establishment of the protected areas system with national parks as its main type in China.

Very high baseline HIV viremia impairs efficacy of non-nucleoside reverse transcriptase inhibitor-based ART: a long-term observation in treatment-naïve patients.

BACKGROUND: It is not completely clear whether a very high pre-therapy viral load (≥ 500 000 copies/ml) can impair the virological response. The aim of this study was to examine the influence of very high baseline HIV-RNA levels on long-term virological responses under one type of regimen. METHODS: A retrospective study was performed based on data from two multicenter cohorts in China from January to November 2009, and from May 2013 to December 2015. Untreated HIV infected adults between 18 and 65 years old were recruited before receiving non-nucleoside reverse transcriptase inhibitor-based regimen. All patients had baseline HIV-RNA levels over 500 copies/ml, good adherence, and were followed for at least 24 weeks. Virological suppression was defined as the first HIV-RNA < 50 copies/ml. Virological failure was defined as any of incomplete viral suppression (HIV-RNA ≥ 200 copies/ml without virological suppression within 24 weeks of treatment) and viral rebound (confirmed HIV-RNA level ≥ 50 copies/ml after virological suppression). Chi-square test, Kaplan-Meier analysis, Cox proportional hazards model and Logistic regression were used to compare virological response between each pretreated viral load stratum. RESULTS: A total of 758 treatment-naïve HIV patients in China were enlisted. Median follow-up time (IQR) was 144 (108-276) weeks. By week 48, rates of virological suppression in three groups (< 100 000, 100 000-500 000 and ≥ 500 000 copies/ml) were 94.1, 85.0, and 63.8%, respectively (P < 0.001). Very high baseline HIV viremia over 500 000 copies/ml were found to be associated with delayed virological suppression (≥ 500 000 vs <  100 000, adjusted relative hazard = 0.455, 95% CI: 0.32-0.65; P < 0.001) as well as incomplete viral suppression (≥ 500 000 vs < 100 000, adjusted odds ratio [aOR] = 6.084, 95% CI: 2.761-13.407; P < 0.001) and viral rebound (≥ 50 000 vs < 100 000, aOR = 3.671, 95% CI: 1.009-13.355, P = 0.048). CONCLUSIONS: Very high levels of pre-treatment HIV-RNA were related with delayed efficacy of NNRTI-based ART and increased risk of treatment failure. More potent initial regimens should be considered for those with this clinical character.

Antiretroviral Long-Term Efficacy and Resistance of Lopinavir/Ritonavir Plus Lamivudine in HIV-1-Infected Treatment-Naïve Patients (ALTERLL): 144-Week Results of a Randomized, Open-Label, Non-Inferiority Study From Guangdong, China.

Dual therapy with lopinavir/ritonavir (LPV/r) plus lamivudine (3TC) has been demonstrated to be non-inferior to the triple drug regimen including LPV/r plus two nucleoside reverse transcriptase inhibitors (NRTIs) in 48-week studies. However, little is known about the long-term efficacy and drug resistance of this simplified strategy. A randomized, controlled, open-label, non-inferiority trial (ALTERLL) was conducted to assess the efficacy, drug resistance, and safety of dual therapy with LPV/r plus 3TC (DT group), compared with the first-line triple-therapy regimen containing tenofovir (TDF), 3TC plus efavirenz (EFV) (TT group) in antiretroviral therapy (ART)-naïve HIV-1-infected adults in Guangdong, China. The primary endpoint was the proportion of patients with plasma HIV-1 RNA < 50 copies/ml at week 144. Between March 1 and December 31, 2015, a total of 196 patients (from 274 patients screened) were included and randomly assigned to either the DT group (n = 99) or the TT group (n = 97). In the primary intention-to-treat (ITT) analysis at week 144, 95 patients (96%) in the DT group and 93 patients (95.9%) in the TT group achieved virological inhibition with plasma HIV-1 RNA <50 copies/ml (difference: 0.1%; 95% CI, -4.6-4.7%), meeting the criteria for non-inferiority. The DT group did not show significant differences in the mean increase in CD4+ cell count (247.0 vs. 204.5 cells/mm3; p = 0.074) or the CD4/CD8 ratio (0.47 vs. 0.49; p = 0.947) from baseline, or the inflammatory biomarker levels through week 144 compared with the TT group. For the subgroup analysis, baseline high viremia (HIV-1 RNA > 100,000 copies/ml) and genotype BC did not affect the primary endpoint or the mean increase in CD4+ cell count or CD4/CD8 ratio from baseline at week 144. However, in patients with genotype AE, the DT group showed a higher mean increase in CD4+ cell count from baseline through 144 weeks than the TT group (308.7 vs. 209.4 cells/mm3; p = 0.038). No secondary HIV resistance was observed in either group. Moreover, no severe adverse event (SAE) or death was observed in any group. Nonetheless, more patients in the TT group (6.1%) discontinued the assigned regimen than those in the DT group (1%) due to adverse events. Dual therapy with LPV/r plus 3TC manifests long-term non-inferior therapeutic efficacy, low drug resistance, good safety, and tolerability compared with the first-line triple-therapy regimen in Guangdong, China, indicating dual therapy is a viable alternative in resource-limited areas. Clinical Trial Registration: [http://www.chictr.org.cn], identifier [ChiCTR1900024611].

X4-Tropic Latent HIV-1 Is Enriched in Peripheral Follicular Helper T Cells and Is Correlated with Disease Progression.

Follicular helper T (TFH) cells have been shown to support productive human immunodeficiency virus type 1 (HIV-1) replication and to serve as a key component of the latent viral reservoir. However, the viral characteristics of this latent reservoir and the clinical relevance of this reservoir remain unclear. In this study, we assessed the tropic composition of latent viruses from peripheral TFH (pTFH), non-TFH memory, and naive CD4+ T cells from individuals with HIV-1 infections on suppressive combined antiretroviral therapy (cART). X4-tropic latent HIV-1 was preferentially enriched in pTFH cells compared to levels in the other two subsets. Interestingly, the ratio of X4-tropic latent HIV-1 in pTFH cells not only was robustly and inversely correlated with blood CD4+ T cell counts across patients but also was prognostic of CD4+ T cell recovery in individuals on long-term cART. Moreover, patients with higher X4-tropic latent HIV-1 ratios in pTFH cells showed greater risks of opportunistic coinfections. These findings reveal the characteristics of latent HIV-1 in TFH cells and suggest that the ratio of X4-tropic latent HIV-1 in pTFH cells is a valuable indicator for disease progression and cART efficacy.IMPORTANCE TFH cells have been shown to harbor a significant amount of latent HIV-1; however, the viral characteristics of this reservoir and its clinical relevance remain largely unknown. In this study, we demonstrate that X4-tropic latent HIV-1 is preferentially enriched in pTFH cells, which also accurately reflects the viral tropism shift. The ratio of X4-tropic proviruses in pTFH cells but not in other memory CD4+ T cell subsets is inversely and closely correlated with blood CD4+ T cell counts and CD4+ T cell recovery rates with cART. Our data suggest that the ratio of X4-tropic provirus in peripheral TFH cells can be easily measured and reflects disease progression and treatment outcomes during cART.

The clinical significance of myeloid-derived suppressor cells in dengue fever patients.

BACKGROUND: Myeloid-derived suppressor cells (MDSCs) play immunosuppressive roles in cancers and some infectious diseases; however, their role in dengue fever (DF) remains unknown. This study evaluated the clinical significance of MDSCs in DF patients. METHODS: This study comprised 178 non-severe DF patients, 20 non-dengue fever (NDF) controls, and 30 healthy donors. The DF patients were divided into the following five groups based on the fever duration from its onset to the day of sample collection: fever duration of 1-2, 3-4, 5-6, 7-8, and > 9 days. Among these DF patients, 14 were monitored for eight days, and their peripheral blood samples were collected every two days. The mononuclear cells were isolated and analyzed using flow cytometry. The correlation between the MDSCs and clinical and immunological indicators of the DF patients was evaluated using Spearman analysis. RESULTS: The count of the peripheral blood MDSCs, especially monocytic MDSCs, of the 178 DF patients were dramatically higher than those of the NDF and healthy controls, and remarkably decreased with the fever duration. Moreover, the MDSC count correlated with some indicators, including the dengue viral load (rho = 0.367, p < .001), body temperature (rho = 0.263, p = .005), prothrombin time (rho = 0.475, p < .001), CD4+ T cell number (rho = - 0.317, p < .001), CD8+ T cell number (rho = - 0.361, p < .001), "programmed cell death protein 1" (PD-1) (rho = - 0.347, p < .001), "T cell immunoglobulin domain and mucin domain-3" (Tim3) (rho = - 0.258, p = .001), interferon-α (IFN-α) (rho = 0.43, p < .001), and "regulated upon activation normal T-cell expressed and secreted" (RANTES) (rho = 0.278, p = .019). Furthermore, the level of arginase-1, but not nitric oxide, was higher in the DF patients than in the healthy controls and was closely related to the number of MDSCs (rho = 0.265, p = .024). CONCLUSIONS: Our study reveals a significant correlation between MDSCs and DF clinical indicators, posing MDSCs as potential target cells for DF treatment.

IL-21 Expands HIV-1-Specific CD8+ T Memory Stem Cells to Suppress HIV-1 Replication In Vitro.

Due to the existence of viral reservoirs, the rebound of human immunodeficiency virus type 1 (HIV-1) viremia can occur within weeks after discontinuing combined antiretroviral therapy. Immunotherapy could potentially be applied to eradicate reactivated HIV-1 in latently infected CD4+ T lymphocytes. Although the existence of HIV-1-specific CD8+ T memory stem cells (TSCMs) is well established, there are currently no reports regarding methods using CD8+ TSCMs to treat HIV-1 infection. In this study, we quantified peripheral blood antigen-specific CD8+ TSCMs and then expanded HIV-1-specific TSCMs that targeted optimal antigen epitopes (SL9, IL9, and TL9) in the presence of interleukin- (IL-) 21 or IL-15. The suppressive capacity of the expanded CD8+ TSCMs on HIV-1 production was measured by assessing cell-associated viral RNA and performing viral outgrowth assays. We found that the number of unmutated TL9-specific CD8+ TSCMs positively correlated with the abundance of CD4+ T cells and that the expression of IFN-γ was higher in TL9-specific CD8+ TSCMs than that in non-TL9-specific CD8+ TSCMs. Moreover, the antiviral capacities of IL-21-stimulated CD8+ TSCMs exceeded those of conventional CD8+ memory T cells and IL-15-stimulated CD8+ TSCMs. Thus, we demonstrated that IL-21 could efficiently expand HIV-1-specific CD8+ TSCMs to suppress HIV-1 replication. Our study provides new insight into the function of IL-21 in the in vitro suppression of HIV-1 replication.

Kinetics of antigen-specific IgM/IgG/IgA antibody responses during Zika virus natural infection in two patients.

Understanding of kinetics of antibody responses is crucial for developing rapid serological tests and studying the mechanisms of Zika virus (ZIKV) infection. Most of the serological diagnostic assays previously published are based on either IgM or IgG titer, little is known on the level of IgA antibody in saliva and urine. In this study, we investigated the kinetics of IgM/IgG/IgA antibody responses in serum, saliva, and urine obtained from two ZIKV infected individuals from as early as the second day of onset of symptoms to as long as 2 years postinfection. Other than detecting robust early IgM response, long lasting IgG response, we discovered strong early IgA response specific for ZIKV in saliva in both patients. This unique observation provides a novel strategy and scientific basis for the development of noninvasive rapid tests for ZIKV infection.

The dengue preface to endemic in mainland China: the historical largest outbreak by Aedes albopictus in Guangzhou, 2014.

BACKGROUND: Dengue was regarded as a mild epidemic in mainland China transmitted by Aedes albopictus. However, the 2014 record-breaking outbreak in Guangzhou could change the situation. In order to provide an early warning of epidemic trends and provide evidence for prevention and control strategies, we seek to characterize the 2014 outbreak through application of detailed cases and entomological data, as well as phylogenetic analysis of viral envelope (E) gene. METHODS: We used case survey data identified through the Notifiable Infectious Disease Report System, entomological surveillance and population serosurvey, along with laboratory testing for IgM/IgG, NS1, and isolation of viral samples followed by E gene sequencing and phylogenetic analysis to examine the epidemiological and molecular characteristics of the outbreak. RESULTS: The 2014 dengue outbreak in Guangzhou accounted for nearly 80% of total reported cases that year in mainland China; a total of 37,376 cases including 37,340 indigenous cases with incidence rate 2908.3 per million and 36 imported cases were reported in Guangzhou, with 14,055 hospitalized and 5 deaths. The epidemic lasted for 193 days from June 11 to December 21, with the highest incidence observed in domestic workers, the unemployed and retirees. The inapparent infection rate was 18.00% (135/750). In total, 96 dengue virus 1 (DENV-1) and 11 dengue virus 2 (DENV-2) strains were isolated. Phylogenetic analysis indicated that the DENV-1 strains were divided into genotype I and V, similar to the strains isolated in Guangzhou and Dongguan in 2013. The DENV-2 strains isolated were similar to those imported from Thailand on May 11 in 2014 and that imported from Indonesia in 2012. CONCLUSIONS: The 2014 dengue epidemic was confirmed to be the first co-circulation of DENV-1 and DENV-2 in Guangzhou. The DENV-1 strain was endemic, while the DENV-2 strain was imported, being efficiently transmitted by the Aedes albopictus vector species at levels as high as Aedes aegypti.

PCB 118-induced endothelial cell apoptosis is partially mediated by excessive ROS production.

Endothelial cell apoptosis, which may alter the integrity of the endothelium and lead to plaque instability, plays a critical role in the development and pathogenesis of atherosclerosis. Exposure of polychlorinated biphenyls (PCBs) is associated with increased risk of atherosclerosis and cardiovascular disease. In our present study, we explored whether exposure to PCB 118 influences endothelial cell apoptosis in vitro and the underlying mechanisms involved. As expected, exposure to PCB 118 increased the intracellular reactive oxygen species (ROS) levels in HUVECs. Increases in apoptosis and Bax/Bcl-2 ratios were observed in PCB 118-treated HUVECs. N-acetyl-l-cysteine (NAC), a ROS scavenger, partially reduced PCB 118-induced apoptosis and Bax/Bcl-2 ratios in HUVECs. Taken together, PCB 118-induced endothelial cell apoptosis was partially initiated by excessive ROS production.